In response to RFA-DA-11-004, we propose in this STTR Phase I application to develop and test a nicotine vaccine utilizing a chemical derivative of the drug, or hapten, coupled to an immunostimulatory, adjuvant-containing liposome. The current approach to curbing nicotine addiction is the use of over the counter nicotine replacement products, but this approach has yielded only modest results. A vaccine approach allows the individual to mount an immune response wherein highly specific antibodies sequester the nicotine while it is still in the bloodstream. The antibody-drug complex can then counteract the reinforcing effects of the nicotine by blunting the ability of nicotine to cross the blood-brain barrier, as well as preventing any detrimental side effects of the drug on the central nervous system. In order to optimize the immune response generated, the liposomal formulations will include selected Toll-like receptor (TLR) agonists as adjuvants. TLRs augment the immune response by activating an inflammatory signaling cascade in the host. Our initial formulations will incorporate the following TLR agonists for testing: MPL (TLR4);loxoribine (TLR7/8) and;an oligonucleotide containing a CpG motif (TLR9). The TLR- containing immunogenic liposomes will be conjugated to the lead nicotine hapten, AM1, which was identified by the Janda laboratory. This hapten will be conjugated to the VesiVax(R) conjugatable adjuvant lipid vesicles (CALV) using a one step reaction. Once prepared and characterized, the lipsomes will be tested for immunogenicity in mice. These Phase I studies will allow us to identify one or more VesiVax(R).-nicotine formulations to optimize and develop into a nicotine vaccine for clinical advancement in the STTR Phase II application. PUBLIC HEALTH RELEVANCE: Nicotine is the most widely used, readily available legal psychostimulant in the world and is highly additictive. The delivery of a vaccine based on a nicotine hapten coupled to an immunogenic liposome formulation represents a significant advancement in curbing nicotine addiction. This innovative approach maximizes the immunogenic potential of the nicotine moiety by formulating it with a Toll- like Receptor adjuvant loaded liposome to elicit high specificity antibodies capable of binding to and sequestering nicotine drug present in the bloodstream. This method could decrease the addictive potential of nicotine by preventing free access to receptors in the brain thus, alleviating one of the largest health concerns in the United States.